The present invention relates to a new process for producing the known 4"-epi-methylamino-4"-deoxyavermectin B.sub.1, a potent insecticide.
2. Brief Description of Disclosures in the Art
The members of the avermectin class of natural products, first isolated.sup.1 (Note: superscripts refer to references which are listed in the specification following the Examples) from the soil microorganism Streptomyces avermitilis, are 16-member lactones possessing a great diversity of functionalities: an L-oleandrose based disaccharide unit, a spiroketal system, a diene and an acid and base sensitive oxahydrindene ring system. The successful commercialization of two members of the class of avermectins (`abamectin`.sup.1, and `ivermectin`.sup.2) due to their potent anthelmintic, insecticidal and acaricidal properties for agricultural and anti-parasitic uses in animals and man represents a great advance in pesticidal natural products.
Among a host of analogues prepared from the avermectins is the relatively new class of 4"-aminoavermectins..sup.3 These aminosaccharide containing avermectins have been shown to have excellent activity against a variety of insect larvae, spider mites and aphids, and the use of 4"-epi-methylamino-4"-deoxyavermectin B.sup.1 benzoate (1a, MK-244, emamectin benzoate) (Scheme 1) as an agricultural insecticide is under investigation..sup.4 ##STR1##
A synthesis of MK-244 (1a) from avermectin B.sub.1 (5) could logically proceed by direct displacement of a suitable derivative of the C.sub.4 "-hydroxyl group. Displacement/inversion of equatorial substituents in carbocyclic tings is normally a difficult task; however, attempted displacement of i-butyl 4-O-mesylate oleandrose (2) with sodium benzoate in DMF leads to ting contraction to the furanoside 3 (Scheme 2)..sup.5a-f Ring contraction with triflate derivatives occurs readily in DMF in the absence of other nucleophiles..sup.5d Sct However, there are reports of successful displacement/inversion reactions with the use of sodium azide in hexamethylphosphoramide (HMPA)..sup.6 The attempted displacement of either the C.sub.4 "-mesylate or -triflate derivative of avermectin B.sub.1 (5) with sodium azide in DMF leads to epimerization at the C.sub.2 position prior to any displacement/rearrangement. ##STR2##
Syntheses of MK-244 (1a) via reductive amination of the 4"-ketone of avermectin B.sub.1 has been reported..sup.3a,7 An alternative synthesis to 4"-epi-amino-avermectins from avermectin B.sub.1 (5) (Scheme 1 ) could involve the removal of the terminal oleandrose sugar, preparation of a suitable amino-oleandrose derivative and it's re-attachment.
Among the syntheses of avermectins,.sup.8 stereocontrol of the 1"-anomeric center (avermectin numbering) in the preparation of the oleandrosyl oleandrose disaccharide has been reported. Nicolaou.sup.8a coupled fluoro 4-O-TBDMS oleandrose with thiophenyl oleandrose using DAST-NBS to give the disaccharide as the .alpha.-anomer in 65% yield. Danishefsky.sup.8b activated the glycal of oleandrose with N-iodosuccinimide in the presence of methyl oleandrose to give a 2'-iododisaccharide with exclusive formation of the .alpha.-anomer. More recently, Ley.sup.8d reported the coupling of an imidazolylcarbonyl oleandrose with acetyl oleandrose in the presence of silver perchlorate to give disaccharide in 62% yield with the formation of 11% of the .beta. anomer; and Mereyala.sup.8e coupled 2-pyridylthio 3-O-acetyl oleandrose with methyl oleandrose in the presence of methyl iodide to give predominantly the .alpha.-anomer. The direct glycosidation of alcohols with thioglycosides using thiophilic reagents generally produces .alpha./.beta. anomeric mixtures with the .alpha.-anomer predominating, but not exclusively. Glycosidations using thiosugars containing equatorial 2-amido.sup.9a-d appendages have long shown excellent stereocontrol due to involvement of a 1,2-acetamido-bridging carbonium intermediate leading to the predominant formation of the .beta.-anomer. In our case, it was postulated that activation of a thio 4-epi-acylamino-oleandrose donor derivative might direct the approach of an oleandrose acceptor unit via a 1,4 bridging intermediate. Due to the axial configuration of the acylamino group, this might result in a high degree of control in the formation of the .alpha.-anomer.